The History of Electrical Stimulation of the Brain

Renato M.E. Sabbatini, PhD

The second half of 19th
century witnessed the development of electrical stimulation, a new technique which became one of the most important
tools scientists could use for the experimental discovery of brain localization of function. This article tells
its history.

Physics had already discovered magnetism and electricity since the end of 17h century, and had gradually developed
several methods to obtain electrical currents whenever they were needed. The term "electricity" had been
coined by William Gilbert (1544-1603), the great Elizabethan scientist, who brought to the world the first systematic
knowledge about the phenomenon of magnetism, which was known since Antiquity, thanks to the exploitation of magnetic
iron rocks. "Elektra"
means amber in Greek, a material used to generate mysterious attractive forces upon attrition. Gilbert became famous
with his book "De Magnete"
(About Magnetism), published em 1600.

The powerful development of experimental physics along the 19th century brought together these two forces of Natures,
electricity and magnetism. They were shown to be intimately related, therefore giving birth to electromagnetism.
The basic studies and theories related to electromagnetism were developed by great physicists such as Hans Christian
Oersted (1777-1851), Michael Faraday (1791-1867) and James Clerk Maxwell (1831-1879).

Hans Christian Oersted

James Clerk Maxwell

Michael Faraday

The Precursors

The history of electrical stimulation as a method for investigating the functions
of the nervous system began with the Italian physician and scientist Luigi Galvani (1737-1798). He discovered that nerves and muscles are electrically excitable,
working on his lab in Bologna, around 1786. In a series of experiments which were bound to revolutionize neurophysiology,
Galvani was able to elicit contractions in the muscles of frogs, by stimulating them or their spinal nerves with
brief jolts of electricity generated by static generators, Leyden jars (a kind of capacitor) and even lightnings.
His stimulation techniques were quite gross, so more sophisticated studies were impossible, particularly those
which demanded the stimulation of tinier areas of tissue. As we will see later on, it was only when physics developed
apparatuses to allow for a more controlled and accurate way of stimulating biological tissue that scientific progress
became more rapid, and that systematic studies of nervous function became possible.

Luigi Galvani, physician from Bologna, the great researcher on bioelectricity

Alessandro Volta, Italian physicist and inventor of the electric pile

Experiments of voltaic stimulation of nerves and muscles by Luigi Galvani in 1786

One of the fundamental steps towards this was achieved by the great Italian physicist
Alessandro Volta (1745-1827). Inspired by the research of Galvani, Volta invented one of the most important tools
for the history of electrical stimulation, the electric pile. He was trying to replicate the results of his friend
(and later, foe) Galvani, and discovered that a constant electromotive force could be generated by putting in contact
two different metals, such as copper and iron (this was his explanation for Galvani's result, denying that animal
electricity was a real phenomenon). He had, then, the idea of building a vertical "pile" of metal disks
separated from each other by disks of felt imbibed in a conductive solution. The voltaic pile, as it was subsequently
called in his honor, was extremely useful for generating a controllable and stable value of electric voltage. Amplitude
was increased or decreased by simply changing the number of identical disks in the pile.

After Galvani's results were confirmed by Alexander von Humboldt and Carlo Mateucci, scientists became convinced
that nerves and muscles, at least, were really electrically excitable, and that they also generated a kind of electricity
by themselves. This could be the basis for a new model of nervous activity. Thus, two questions became highly important
at the time:

Are the spinal chord and brain substances also electrically excitable?.

Could the stimulation of different points in the brain generate different effects.or
in different parts of the body?

The first question was related to whether the central nervous system worked accordingly
to the new electrical model, too; while the second question addressed the ages-old problem of brain localization
of function, a quest which was in vogue in neuroscience since Franz Joseph Gall had proposed it through his
(false) doctrine of phrenology.

We should not forget, however, that around that time (1800), practically nothing about the encephalon was known
besides its gross anatomical structure and the existence of white and gray matter. Science still had no idea whatsoever
about its constitution in terms of fibers, cells, how they worked, etc. The relationship of nerves to particular
areas in the brain and spinal chord were also a mistery. Focal electrical stimulation, then, could open the doors
to the experimental investigation and fact-finding about all this.

Is the Brain Excitable?

The first scientist to test this hypothesis was a nephew and collaborator of Galvani,
named Giovanni Aldini (1762-1834). In 1802, Aldini did a number of bizarre experiments. In Bologna, London and
elsewhere, he used the bodies of recently hanged and decapitated prisoners to apply electrical currents, using
the same methods that his uncle Galvani had employed to stimulate nerves and muscles of animals. Aldini attracted
the attention of the population and the media by carrying out public shows. To gasps of horror and fascination
of the populace, he demonstrated how electrical stimulation applied in the surface of the head and members evoked
responses such as blinking and opening the eyes, facial grimaces, and tongue, eye and limb movements. Aldini constructed
enormous voltaic piles for this, some of them having more than 100 elements. He wanted to prove that he was stimulating
the brain, but in fact he was not, because electrical current, however strong, would be blocked by the thick bones
of the skull. He was actually stimulating the muscles directly.

Giovanni Aldini (1762-1834)

Right: Experiments by Aldini with electrical stimulation of cadavers using voltaic piles (1802).

Anyway, one of the unexpected consequences of Aldini's grotesque "experiments"
was the gothic romance "Frankenstein, or Modern Prometheus",
published in 1818. Its writer, Englishwoman Mary Wollstonecraft
Shelley (1797-1851), was exceedingly impressed with the possibility of
generating life in dead tissues by means of electrical stimulation. In discussions with his husband-poet Percy
Shelley (1792-1822) and famous writer and poet Lord Byron (1788–1824), Mary Shelley famously said "Perhaps, a corpse would be reanimated; galvanism had given token of such things.". Many serious scientists (as well as inumerable charlatans) became intrigued with
this possibility and galvanism turned out to be a sinonym of all sorts of attempts at ressuscitating by electricity and as a way of
curing everything, from gout to mental disease (Charles Darwin himself, a serious naturalist, succumbed for a time
to the quack "electrical treatment" prescribed by a doctor in Scotland, to treat his chronic gastrointestinal
ills, by wearing on occasions a shock-giving belt).

In this point of our history, it was natural to arise the idea to apply electrical stimulation directly to the
exposed brain. The first to do this was another Italian (Italy was at the time one of the leading countries in
physiology and physics), an anatomist, physician and scientist named Luigi Rolando (1773-1831). His name is mostly
known by medical students from the Rolandic
fissure, or central fissure, which separates the frontal from the parietal
lobes of the brain, and is visible in the surface of the cortex. In 1809, Rolando carried out several experiments
of lesion and stimulation of the surface of central nervous structures. Using a voltaic pile and crude electrodes,
he obtained limb movements, which became stronger in the vicinity of cerebellum. He erroneously concluded that
this structure was the brain's "source of vital motor energy". His pioneerism was assured, though.

Rolando was thus able to give a satisfactory answer to the first question only, i.e., he proved that the central
nervous system was indeed electrically excitable, and that voltaic stimulation could be a valuable research tool
for exploring brain functions. The answer to the second question would have to wait 40 years, until best stimulation
techniques could be discovered, with a finer control over duration, intensity and area of stimulation..

Carlo Mateucci,
Italian physiologist

Emil du Bois-Reymond,
German physiologist

Claude Bernard,
French physiologist

These techniques were developed on the basis of the advance of knowledge about
electromagnetism. Between 1845 and 1850, other electrophysiologists, such as the Italian researcher Carlo Mateucci
(1811-1868), and the German researcher Emil Heinrich du Bois-Reymond (1818-1896), perfectioned a great diversity
of devices and techniques to carry out single or repetitive stimulations, with short pulses or trains, and a finer
control over current intensity and duration. They used electromagnetic switches and inductors, finally substituting
the galvanic stimulation with voltaic currents and the primitive tools of Galvani, Volta, Aldini and Rolando. In
the inductor stimulator, intensity and duration of the electrical current are controlled by the rapid linear displacement
of a wire coil over a magnetic core. Repetitive trains of stimulation with a precise onset and offset were generated
by rotary switches and mercury pool switches, or electromechanical metronomes. In honor of Michael Faraday, the
first physician to investigate in depth the generation of electrical currents by means of changing magnetic fields,
this new type of stimulation was named as "faradic", in contraposition to the "galvanic" or
"voltaic" method (curiously enough, the term "galvanic" was created by Volta, and Aldini, a
bitter foe of Volta, created the term "voltaic". So much for Italian scientific politics!).

French physiologist Claude Bernard (1813-1878) was another scientist who was busy creating new and more precise
tools for electrical stimulation. In 1856 he developed a peculiar instrument, which incorporated a miniature voltaic
pile to a pair of metallic insulated tweezers. He used these in his awarded classical investigations on the action
of curare, a South American plant poison used for arrows, in the blocking of the neuromuscular junction.

In recognition of all these contributions, made in the relatively short period of 60 years of scientific evolution,
neuroscience historians consider that Luigi Galvani was the father of neurophysiology, Claude Bernard was the fater
of experimental physiology, and DuBois-Reymond was the father of experimental electrophysiology.

Unfortunately, the experiments by these forefathers of neurophysiology were entirely made within the limits of
peripheral nervous system. It was clear that, until the middle of the 19th century, despite Rolando's experiments,
many neuroscientists believed that the brain was insensitive to external changes and was electrically inexcitable.
This was going to change dramatically under the impact of new animal experiments using electrical stimulation.
.

Animal Experimentation

The pioneering work of mapping the brain cortex with electrical stimulation was
done in 1870 by two German physiologists, Gustav Theodor Fritsch (1838-1927) and Julius Eduard Hitzig (1838-1907).
They carried out experiments of localized electrical stimulation of the brain cortex of several animals, specially
dogs. Their main work was published as an article. This classic work of neuroscience was named Über die elektrische Erregbarkeit des Grosshirns
(About the Electrical Excitabilty of the Brain).

Fritsch and Hitzig obtained in animals contralateral movements of the head, neck and limbs upon stimulating several
points in the cortex. This contralaterality of movement was already known since French physiologist Pierre Flourens (1794-1867) had lesioned and stimulated
mechanically and chemically the brain lobes of pigeons and rabbits, between 1824 and 1827. More that that, however,
they achieved a finer mapping of cortical motor function, because they noted that movements in the rear limbs were
obtained by stimulation of the upper parts of the frontal cortex, while movements of front limbs and neck were
obtained by stimulation of the lower (more ventral) parts of the cortex. Thus, a true somatotopy existed (from
the Greek soma=body, and topos=site). We can truthfully say that this was
one of the most important findings of the history of neuroscience, because it answered the second question, i.e.,
cerebral localization of function was demonstrable, and that the electrical stimulation in anesthetized or semi-anesthetized
animals was extremely useful to carry out mapping studies, at least on the surface of the cortex, which was easier
to access at the time. Their publication generated a lot of scientific excitement and inspired a great deal of
similar experiments.

The giant of this research line was to be the British physiologist and physician David Ferrier (1843-1924), who, inspired on the
experiments by Fritsch and Hitzig, carried out a number of more advanced and systematic experiments, around 1875.
He stimulated with a higher precision the cortex of dogs and monkeys. In the later, he was able to draw a map with
29 different functions across the cortex, which he identified and numbered. In this way, Ferrier created the basic
methodology to be used for the next three quarters of century.

Ferrier most audaciously transposed his results with monkeys to the human brain, by producing an analogous map
of functional localization. This was experimentally unsubstantiated until the first decades of the next century,
but it was very important to launch a new era in the medical applications of cerebral localization studies, especially
for neurosurgery. Neurologists and neurosurgeons could now predict the localization of a tumor or lesion on the
brain, on the basis of its consequences on the neurologial examination of motor and sensory functions. Ferrier
was inspired in this pioneering endeavour by his teacher and friend the great forefather of British neurology,
John Hughlings Jackson
(1835–1911). He was the preponent of the so-called doctrine of hierarchical organization of brain functions, which
became the basis of clinical neurological practices afterwards. By studying brain lesions which were associated
to motor epileptical manifestations, Jackson was able to discover several functional areas of the brain, and Ferrier
had the strongest desire to prove that Jackson was right, and that this knowledge would be useful for practical
purposes.

Ferrier was also a pioneer in the combined use of lesion and stimulation techniques in the same areas of the brain,
with the aim of testing consistent hypothesis about the proposed maps. He lesioned the areas in dog and monkey
brains which, upon stimulation, produced some movements. Consistency of mapping could be achieved when the same
voluntary or involuntary movements would be lost due to the lesions. In dozens of classical experiments, Ferrier
was able to prove this assertion several times, convincing him on the reality of an utmost one-to-one mapping of
function in the brain. He was opposed by many neuroscientists, who were still reluctant to believe that such preciseness
of localization was real. Many defended the idea that the cortex was equipotential in function and had no specialization.
Ferrier was involved in a famous scientific dispute with German neurophysiologist and neurologist Friedrich Goltz (1834-1902), who could not observe
focal disruption of motor and behavioral functions in dogs, despite extensive cortical lesions. Ferrier was able
to demonstrate inadequacies and experimental errors in Goltz's experiments and publicly won the dispute.

A few decades later, Sir Charles Scott Sherrington (1852-1952), a British physiologist, working with young American
neurosurgeon Harvey
William Cushing (1869-1939), did a more extensive motor corticl mapping
study in great apes (gorillas an chimpanzees), in 1901, corroborating and extending Ferrier's findings. o os resultados
de Ferrier. They also made the first experimental proof that the cortical area which corresponded in humans to
speech expression (the so-called Broca's area, thus named because it was discovered in clinical cases studied by
French neurologist and anthropologist Paul Pierre Broca (1824-1880)). The area demarcated
by Sherrington and Cushing was the same which generated an elevation of vocal cords in the gorilla.

Mapping the Human Brain

Sherrington and Cushing obtained a more detailed mapping because the stimulation
techniques were much more perfectioned at the time. By working with the great apes for the first time, which are
the closest evolutionary relatives to human beings, they opened up the pathway for investigations of human brain
by using electrical stimulation.

The human brain was for centuries considered a "forbidden territory" to the surgeon's scalpel and the
experimentalist's hand, due to religious, ideological and medical prejudices. It was only in the second half of
the 19th century that neurosurgeons had the courage to operate on intracranial tumors and other lesions. Despite
ethical problems and the great danger of infection and death, electrical stimulation could be used because it avoided
irreversible lesions in the brain. It became even more acceptable when advances in surgical asepsis, anesthesia
and post-surgical care allowed for safer and longer interventions.

The first experimental electrical brain stimulation in human beings happened almost simultaneously with Ferrier's
first investigation, in 1874, or about 70 years after Aldini and Rolando. An American neurologist named Roberts
Bartholow (1831-1904) stimulated a pacient suffering from a skull bone erosion, thus exposing the surface of the
underlying dura. He stimulated just two points, which luckily were on the motor cortex. In response, he got movements
in the inferior limbs of the patient, on the other side of the estimulated cortex. Despite Bartholow's crude and
limited experiments, he could also answer the second question for the human brain.

Roberts Bartholow (1831-1904)

Experimental investigations of this sort should have to wait until the beginning of the next century. The German
neurosurgeon Fedor Krause (1857-1937) was the first to do this, in a absolutely remarkable feat, due to its extension,
systematics and audacity. By 1902 he already had experimented with electrical stimulation of the exposed brains
of 22 patients, which were operated for other purposes. Posteriorly, Krause expanded his causistics, and in 1912
he had the astounding (for the time) number of 142 cases.

Krause obtained for human brains exactly the same results regarding localization of function which were obtained
with animal experiments in monkeys, apes, dogs, etc. A first glimpse on the cortical organization of the motor
system was now possible, thanks to the tool of electrical stimulation. Krause was also the first one to demonstrate
that there seemed to exist a proportionality between the finess of movement of the stimulated muscle group and
the size of the corresponding cortical area. It was only later that Canadian neurosurgeon Wilder G. Penfield proved
this in a conclusive and more detailed manner. Krause's approach was extended to sensorial cortical mapping by
another great German neurosurgeon, Otfrid Foerster (1878-1941), with whom Penfield trained surgical techniques.

At the same time, in 1902, a formidable advance to support experimental investigations
of brain localization studies was achieved by the invention of the stereotactic method, by the British physiologist
and surgeon Sir
Victor A.H. Horsley (1857-1916) and his colleague Robert Clarke. By using
a cartesian coordinates system in three dimensions and a specially contrived apparatus, neurophysiologists could,
for the first time, map the effects of brain stimulation and lesion with millimetric accuracy. Reaching hidden
and deep structures within the brain, such as the limbic system, basal ganglia, brainstem, cerebellum, hipothalamus
and thalamus, etc. was for the first time possible.

In the beginning of the 20th century, electrical stimulation equipments were still
essentially electromechanical in conception, but they had evolved quite a bit. They were portable, powered by dry
batteries and had variable resistors (rheostats) to control precisely the amount of current or voltage to be delivered
to live tissues. They had also incorporated simple galvanometers in order to calibrate the currents being delivered,
as well as rapid-action electromechanical controls for stimulus repetition.

In the 1920s, however, the electronics revolution led to the development of much more sophisticaded stimulus generators.
Physiologists could now use different waveforms (rectangular, sinusoidal, sawtooth, etc.), with fine control over
intensity, duration of pulses or frequency, repetition, delay, polarities, etc., in complex combinations which
could also be synchronized with electrical recording devices such as oscilloscopes, EEG machones, kimographs, and
so on.

The most advanced clinico-experimental studies with awake humans were carried out between the years of 1930 and
1950 by the famous American-Canadian neurosurgeon Wilder G. Penfield (1891-1976), who later became director of
the Neurological Institute of Montréal. Working with valuable collaborators such as Herbert H. Jasper (1906-1999) and Theodore B. Rasmussen (1910-2002), Penfield used
the same approach of his predecessors Krause and Foerster, in a much larger scale. Penfield perfectioned the technique
to be used in conjunction with brain surgeries, usually temporal lobectomies which were performed to eliminate
epileptic foci, such as scars or tumors. The patient received only a regional anesthesia and was alert during the
whole procedure, so that Penfield could stimulate several spots on the the surface of the exposed cortex and ask
the patient about what he or she were feeling. Besides the expected reactions regarding motor and sensory projections
in the cortex, Penfield was very surprised that complex memories, speech and emotions could be elicited by the
focal brain electrical stimulation. It seemed that these points were some kind of "triggers" for activating
huge neuronal circuits. It was for the first time evidenced, therefore, that the temporal, parietal and other so-called
associational cortices were involved in the integration of many higher brain functions, and these functions were
distributed according to an intrinsic organizational logic.

Penfield was also the first neuroscientist to explor and map in great detail the
motor and sensory somatotopic features of the primary projection and command areas. He thus was able to corroborate,
in conclusive form, how these features were organized, how they related to the body, etc. Penfield became world-reknown
by his ample documentation of the proportionality of cortical areas to the degree of function, like precision of
muscle movement, densities of sensory receptors, etc. As a synthesis of his results, he drew maps which were denominated
"homunculi", or miniature representations of the body areas in the surface of cortex. These homunculi
appeared then, as grotesquely deformed pictures of the human body, causing great impression upon neuroscientists
and the media. For example, the motor homunculus has very large areas devoted to the mouth and tongue, as well
as the thumb area (regions of very complex and fine movements), while the areas connected to the buttocks and thights
are disproportionately smaller. In the sensorial homunculus, the lips and the fingertips have the greater areas,
because they have the largest number of sensory receptors per square centimeter than any other areas of the body.
The pioneering research of the Penfield group was summarized in a seminal book, "The
Cerebral Cortex of Man. A Clinical
Study of Localization of Function" (1950), which he co-authored with
Theodore Rasmussen.

Aparelho estereotáxico para humanos, por Lars
Leksell (1949)

Penfield got all these data about the functional organization of the brain basically by using cortical surface
electrical stimulation, and without using stereotactical methods, since no device specifically built for human
beings was available at the time.

In the 1940s, however, a number of stereotactic devices for neurosurgery in humans began to be developed, such
as one by American neurologists Spiegel e Wycis, in 1947, and another by the Swedish neurosurgeon Lars Leksell (1907-1986), in 1949 (which was different,
because it used a polar coordinate system instead of an orthogonal one, such as the original Horsley-Clarke apparatus).

The stereotactic methods for the human brain led to a great increase in the number of clinico-experimental studies
and surgical treatment methods. One of its first applications was pallidectomy, or the surgical ablation of a part
of the globus pallidus, a subcortical nucleus of the extrapiramidal system (basal ganglia), which controls parts
of the motor system. It was proved that the lesion of this area in patients with Parkinson's disease led to considerable
improvements in its signs and symptoms, since it restored the excitation/inhibition equilibrium which was disrupted
by the typical neuronal death in the substantia nigra, another part of the extrapiramidal system. It was the first
effective surgery for a neurodegenerative disease.

The electrical stimulation of the brain of the awake patient is still in use today in order to determine active
zones (such as in an epileptic focus), before proceeding to the surgery (for more detais on functional neurosurgery,
please see my article on the history
of psicosurgery).